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Increasing rates of invasive candidiasis caused by non-albicans Candida species have been reported worldwide. Particular concerns have been raised for C. parapsilosis because of reduced in vitro susceptibility to echinocandins. We identified 212 patients with invasive candidiasis due to non-albicans Candida species (≥5 cases per species) in 5 clinical trials of caspofungin monotherapy from the pharmaceutical sponsor's (Merck and Co., Inc.) database: 71 cases were caused by C. parapsilosis, 65 by C. tropicalis, 54 by C. glabrata, 10 by C. krusei, 9 by C. guilliermondii, and 5 by C. lusitaniae. One hundred sixty-seven cases caused by C. albicans were also identified. Efficacy was assessed at the end of caspofungin therapy. Success (favorable overall response) required favorable clinical and microbiological responses. The mean APACHE II scores were 16.5 in the non-albicans group and 15.7 in the C. albicans group. Neutropenia at study entry was more common in the non-albicans group (12%) than in the C. albicans group (5%). The median duration of caspofungin therapy was 14 days in both groups. The success rates were 77% in both groups and at least 70% for each non-albicans species: 74% for C. parapsilosis, 71% for C. tropicalis, 85% for C. glabrata, 70% for C. krusei, 89% for C. guilliermondii, and 100% for C. lusitaniae. The times to negative blood culture were similar for the various species. The overall mortality rates were 26% in the non-albicans group and 29% in the C. albicans group. Drug-related serious adverse events and discontinuations due to caspofungin toxicity were uncommon. Although the sample sizes were limited, caspofungin demonstrated favorable efficacy and safety profiles in the treatment of invasive candidiasis caused by the following non-albicans Candida species: C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, C. guilliermondii, and C. lusitaniae.
Candida albicans remains the most common pathogen isolated in invasive candidiasis; however, increasing rates of candidemia caused by non-albicans Candida species, including C. tropicalis, C. glabrata, C. parapsilosis, and C. krusei, have been reported worldwide (16). Non-albicans Candida species accounted for over half the documented cases of candidemia in several studies from Latin America, Europe, and the United States (5, 8, 16), and the prevalence of different species varies substantially from region to region (15, 16). Some of these species are relatively less susceptible than C. albicans to fluconazole. Specifically, C. krusei is inherently resistant and C. glabrata is routinely less susceptible to fluconazole (7, 17). The current treatment guidelines for invasive candidiasis issued by the Infectious Diseases Society of America (IDSA) recommend the use of an echinocandin for infections caused by these 2 species (13). Conversely, in vitro studies have shown that C. parapsilosis and C. guilliermondii are less susceptible to the echinocandins than are other Candida species (10, 11, 18), but the clinical implications of these findings are not clear.
Caspofungin, a member of the echinocandin class, is fungicidal against most Candida species, having demonstrated activity against C. albicans, C. tropicalis, C. parapsilosis, C. krusei, C. glabrata, and C. lusitaniae (1, 3). Caspofungin targets the fungal cell wall, thereby retaining activity against clinical isolates with documented resistance to either the azoles or the polyenes (1, 3). Efficacy results from comparative trials have shown caspofungin to be an effective first-line agent for invasive candidiasis (4, 12). Although the activity for caspofungin against non-albicans Candida species in these studies was encouraging, the extent of efficacy data for each species was often limited (≤10 patients per treatment arm). To gain a better understanding of the efficacy of caspofungin in patients with non-albicans Candida infection, we performed a retrospective post hoc review of the current Merck database to identify all caspofungin-treated patients with invasive candidiasis caused by non-albicans Candida species. The results are described in this report relative to results for patients with invasive candidiasis caused by C. albicans.
Data from patients receiving caspofungin for the treatment of invasive candidiasis are available from 5 phase II/III clinical studies in the Merck database (Table (Table1),1), 2 of which are comparator-controlled trials (protocols 014 and 801) (4, 12) and 3 of which are noncomparative studies (protocols 024, 045, and 043) (6, 9, 19). All 5 studies required that patients had proven invasive candidiasis, as defined by the consensus definitions from the European Organization for the Research and Treatment of Cancer (EORTC) and the Mycoses Study Group (MSG) (2). The one notable exception was the allowance for patients with probable cases of chronic disseminated candidiasis in protocol 045 (6). Patients received caspofungin as monotherapy in all of these studies; details of the specific treatment regimens for each study are provided in Table Table1.1. In general, patients were treated with caspofungin for at least 10 days, and all antifungal therapy (including subsequent oral fluconazole) was administered for at least 14 days after the last positive culture of a Candida sp. from blood or another normally sterile body site. In all studies, careful management of preexisting catheters in patients with candidemia was required. Prior to the initiation of study therapy, all peripheral intravenous or intra-arterial catheters were to be removed and all central venous catheters were to be removed or changed over a guide wire. Patients in whom these catheters were not removed are discussed in the original reports (4, 6, 9, 12, 19).
In all studies, efficacy in all patients who had a confirmed diagnosis of invasive candidiasis and received at least 1 dose of caspofungin therapy (referred to as the modified-intention-to-treat population [6, 9, 12, 19] or the full-analysis-set population ) was assessed. In all trials, the primary efficacy measure was a favorable overall response at the end of caspofungin therapy; this required a favorable clinical response and a favorable microbiological response. A favorable clinical response was defined as resolution (complete response) (4, 6, 12) or improvement (partial response) (9, 19) of all signs, symptoms, and radiographic abnormalities attributed to Candida infection. A favorable microbiological response required clearance of Candida from follow-up cultures, including negative results for Candida in blood cultures at the end of caspofungin therapy in patients with candidemia. For patients with nonblood candidiasis for whom a follow-up culture could not be obtained, presumptive eradication (i.e., both clinical and radiographic resolution of infection) was considered a favorable microbiological response. Relapse assessments varied by trial; therefore, for this analysis, relapse was assessed at 2 weeks and 4 to 8 weeks after the end of therapy in all patients for whom the proper follow-up information was available.
In all studies, adverse events were collected from all patients for the evaluation of safety. Investigators identified the seriousness, causality, and action taken on study therapy for all clinical and laboratory adverse events during the treatment period and for ≥14 days posttreatment. Adverse events that were considered by the site investigator to be definitely, probably, or possibly related to study therapy were classified as drug related.
For this post hoc analysis, all patients with a confirmed case of invasive candidiasis due to non-albicans Candida species were identified, provided there were at least 5 cases of infection for that particular species. The data for patients in each non-albicans group are shown as a separate column in the tables, followed by a column for the total non-albicans group. Data for patients with mixed infections caused by 2 or more non-albicans species are shown separately in each non-albicans group but are only listed once in the total non-albicans column. All patients with invasive candidiasis due to C. albicans were also identified and included. Data for patients with mixed infections caused by C. albicans and a non-albicans Candida species are presented separately under each species. Efficacy was assessed irrespective of caspofungin dose because prior studies failed to demonstrate a benefit of higher doses relative to results obtained with the standard 50-mg daily maintenance dose (4, 6).
The design and sample size of this analysis were not intended to test specific hypotheses with regard to efficacy or safety. This retrospective post hoc analysis was predominantly designed as a descriptive comparison of the results across the different Candida groups. All different analyses and subgroup assessments, including tabular displays, were predefined by the authors prior to the compilation of the data. For the primary efficacy outcome (overall response at the end of caspofungin therapy), a 95% confidence interval (CI) was calculated as an exact CI based on the binomial distribution. Assuming a sample size of 50 patients for each Candida species, the study could rule out observed differences (based on nonoverlapping 95% CI) between groups of 30 percentage points. For those groups with at least 10 patients with candidemia, a Kaplan-Meier analysis was used to assess any differences in the time to negative blood cultures; the log-rank chi-square statistic was also calculated.
This post hoc analysis focused predominantly on the results from the Merck database for caspofungin. Of note, the results from a large, prospective study of caspofungin versus micafungin in invasive candidiasis were not included (14) due to the unavailability of the full data set at the Candida species level. A sensitivity analysis which includes the primary efficacy results from this additional study combined with the results of the 5 studies from the Merck database (4, 6, 9, 12, 19) has been included in Results.
In these 5 studies, a total of 212 patients with invasive candidiasis caused by 6 different non-albicans Candida species (Table (Table2),2), including C. glabrata (n = 54), C. guilliermondii (n = 9), C. krusei (n = 10), C. lusitaniae (n = 5), C. parapsilosis (n = 71), and C. tropicalis (n = 65), were identified. Two patients had mixed infections caused by 2 non-albicans Candida species, including one patient with C. guilliermondii and C. parapsilosis infection and another patient with C. glabrata and C. krusei infection. Data are also available for 167 patients with invasive candidiasis caused by C. albicans who were in these 5 studies. The distribution of patient demographics was generally similar in the combined non-albicans group and the C. albicans group. The median APACHE II score was between 15 and 17 for all species except for C. krusei and C. lusitaniae. APACHE II scores at study entry were higher in patients with C. lusitaniae infection than in any other group, but the number of patients with this species was limited. Patients with C. guilliermondii, C. krusei, or C. tropicalis infection had higher rates (each >20%) of neutropenia than the other groups at study entry. Across the combined non-albicans group and the C. albicans group, the most common risk factors were broad spectrum antibiotics, followed by major surgery, total parenteral nutrition, and active malignancy. Candidemia was the most common site of infection in all groups, ranging from 69 to 100% of patients. Approximately 20% of patients with C. glabrata or C. krusei infection had intra-abdominal abscess.
Caspofungin was predominantly dosed at 50 mg daily (following a 70-mg loading dose on day 1) in adults or 50 mg/m2 daily (following a 70-mg/m2 loading dose on day 1), with the maximum not to exceed 70 mg, in pediatric patients; these regimens were used in 74% of patients with non-albicans Candida infection and in 72% of those with C. albicans infection. The remaining patients (all adults) received caspofungin at 100 or 150 mg daily (Table (Table3).3). The duration of caspofungin therapy ranged from 1 to 57 days (median, 14 days) and was generally similar across the different groups (Table (Table33).
At the end of caspofungin therapy, a favorable overall response was achieved in 70% to 100% of patients with non-albicans infections. Notably, a response rate of 74% (46/65) was seen in patients with infections caused by C. parapsilosis (Table (Table4).4). For comparison, the success rate was 77% in the 167 patients with C. albicans infection from these same 5 studies. Response rates by site of Candida infection or by reason for study entry (primary or salvage treatment) were generally similar across the different species. Among neutropenic patients, the response rate was somewhat lower in patients with C. tropicalis (6/14, 43%) or C. albicans (2/8, 25%) infection than in patients with the other non-albicans Candida species.
Reasons for unfavorable responses were generally similar across the Candida species. One notable finding was that a slightly higher proportion of patients with C. parapsilosis (12/70, 17%) had persistently positive cultures listed as the primary reason for failure at the end of study therapy than was the case for groups with other Candida spp., among which the proportions of patients with persistently positive cultures were 10% (1/10) with C. krusei, 8% (14/166) with C. albicans, 5% (3/65) with C. tropicalis, and 2% (1/54) with C. glabrata. However, this finding was not confirmed when an analysis evaluating the time to a negative blood culture was performed in patients with candidemia. In those groups with at least 10 patients with candidemia, the median times to achieving a negative blood culture for C. glabrata, C. parapsilosis, C. tropicalis, C. krusei, and C. albicans were 2.0, 2.5, 3.0, 3.5, and 5.0 days, respectively (Fig. (Fig.1).1). The log-rank chi-square statistic was not significant (P = 0.522), suggesting that there was no difference among the Candida species with respect to time to achieve a negative blood culture. Among these same groups, an assessment was also made to determine the proportion of patients with persistent candidemia at 72 h after the beginning of caspofungin therapy. The proportions were similar across the 4 non-albicans groups and the C. albicans group.
At 2 weeks after the end of caspofungin therapy, relapse of invasive candidiasis occurred in 3% of patients in the combined non-albicans group and 4% of patients in the C. albicans group. The relapse rates at 4 to 8 weeks after the end of therapy were 6% and 8%, respectively (Table (Table44).
Mortality from all causes was 26% across the combined non-albicans group and 29% in the C. albicans group (Table (Table4).4). Mortality was slightly higher among patients with C. tropicalis (38%) or C. krusei (40%) infection. The mortality rate in patients with C. parapsilosis (20%) was lower than the mean overall mortality but was comparable to the rate in patients with C. glabrata infection (20%) and higher than that in patients with C. guilliermondii infection (11%).
A sensitivity analysis was performed which included the primary efficacy results from the caspofungin treatment group in the caspofungin versus micafungin study of invasive candidiasis (14). With the inclusion of this data, the observed overall response rates for caspofungin against each of the 5 most common Candida species remain above 70% (Table (Table55).
Serious drug-related adverse events occurred in 2 patients (1%) with non-albicans Candida infection (one with C. glabrata and one with C. tropicalis infection) and 2 patients (1%) with C. albicans infection. Caspofungin therapy was discontinued due to a drug-related adverse event in 4 patients (2%) with non-albicans Candida infection (2 with C. tropicalis, one with C. glabrata, and one with C. parapsilosis) and 3 patients (2%) with C. albicans infection. All serious drug-related adverse events and drug-related adverse events leading to discontinuation of caspofungin were distinct terms; no specific adverse event occurred in more than 1 patient.
Candida species other than C. albicans account for 40 to 55% of yeast bloodstream infections worldwide (16). Notably, C. glabrata, C. parapsilosis, and C. tropicalis are the most commonly recovered non-albicans species overall, accounting for 15%, 15%, and 9%, respectively, of all candidemia cases in the SENTRY antimicrobial surveillance program (17). Although it is encountered less frequently, C. krusei is also an important non-albicans species due to its inherent resistance to fluconazole (7, 17). To better understand the efficacy of caspofungin against non-albicans Candida species, we utilized data from 5 clinical studies to examine patient outcomes in 212 cases of invasive candidiasis caused by these 4 species (C. glabrata, C. parapsilosis, C. tropicalis, and C. krusei) and 2 other less common species (C. guilliermondii and C. lusitaniae).
In these 212 patients, success rates were generally high across the various non-albicans species, with a minimum success rate of 70% for each of these species. For comparison, a success rate of 77% was seen in the 167 patients with C. albicans infection from these same 5 studies. Even in specific patient subgroups, success was seen for the various non-albicans groups. Among patients with a non-albicans Candida infection, favorable responses were seen in patients with underlying neutropenia, patients with less common forms of invasive candidiasis, and patients receiving caspofungin as a second-line (salvage) treatment option.
Particular attention has been focused on those non-albicans species which have been reported to be less susceptible to the echinocandins, namely, C. parapsilosis and C. guilliermondii (10, 11, 18). Recent IDSA guidelines recommend that patients with an infection caused by C. parapsilosis should be treated with fluconazole, although the continuation of an echinocandin is reasonable for those patients showing clinical and microbiological improvement following initial treatment with an echinocandin (13). In this analysis, the success rate among patients with a C. parapsilosis infection was 74%, and the time to clearance of infection from the bloodstream and the rate of relapse in this group were comparable to those seen with other Candida species. Additionally, the success rate was 89% in patients with a C. guilliermondii infection. Even though the baseline APACHE II scores in patients with C. parapsilosis or C. guilliermondii were comparable to those seen with other species, the overall mortality with these 2 species was only 19%. This finding may attest to the less virulent nature of these 2 pathogens.
The observed safety profile of caspofungin in patients with non-albicans Candida infection was generally similar to that in patients with C. albicans infection. In both groups, serious drug-related adverse events and discontinuations due to drug-related adverse events were uncommon. About 25% of the patients in this analysis received caspofungin at higher than approved doses. Previous studies have shown that the safety profile of caspofungin at these higher doses is similar to that observed for the standard regimen (50 mg daily after 70 mg on day 1) (4, 6).
This analysis has several notable limitations. First, efficacy was assessed irrespective of different doses of caspofungin. Although this approach was justified by the knowledge that the overall efficacy of caspofungin across different doses in adults (50 to 150 mg daily) (4, 6) and pediatric patients (50 mg/m2 daily) (19) was comparable, differences within patient subgroups may have been influenced by the chosen dose. Second, these 5 studies were conducted at different centers and over different time periods. The efficacy against different species may have been influenced by site-specific differences at these different centers over time. Third, this analysis was conducted as a post hoc analysis. The combination of the data across these 5 studies was not predefined in any of the protocols or statistical analysis plans for these different studies. A final limitation of the current analysis is that it does not include all clinical studies of caspofungin in the treatment of invasive candidiasis conducted to date. Particularly, the results from a large, prospective study of caspofungin versus micafungin in invasive candidiasis were excluded from all analyses because the results of the baseline characteristics, demographics, duration of therapy, and safety were summarized at the treatment group level and not the species level. A major strength of our analysis is that all the detailed data across these different indices have been included at the Candida species level, thereby allowing for a more accurate assessment of the efficacy of caspofungin for each of the different Candida species without bias to potential underlying factors. Nevertheless, a sensitivity analysis was also performed with the inclusion of the caspofungin primary efficacy data from the caspofungin versus micafungin study (14). The inclusion of this additional study does not significantly change the findings seen in our analysis.
Although the present study is still underpowered to definitely solve concerns that have arisen from in vitro data, the results of this study suggest that caspofungin provides therapeutic efficacy in patients with invasive candidiasis caused by C. parapsilosis, C. tropicalis, C. glabrata, C. krusei, C. guilliermondii, and C. lusitaniae. Although the number of cases was limited, the observed efficacy of caspofungin in patients with C. parapsilosis infection remained over 70%. Caspofungin also manifested a favorable safety profile in patients with non-albicans Candida infection, with very few serious drug-related adverse events or discontinuations because of toxicity. It is important to remember that no single randomized clinical trial with sufficient power to evaluate possible differences in the efficacy of antifungal drugs to treat non-albicans Candida species has been conducted, and we expect that such a study is not likely to be performed in the near future. In this scenario, our study adds relevant data to the field and provides information suggesting that caspofungin may be used as first-line therapy for invasive candidiasis caused by non-albicans Candida species, even in regions where C. parapsilosis is highly prevalent.
Funding for this study was provided by Merck & Co., Inc.
Potential conflicts of interest include grants for research and consulting and speaker's bureau fees received by A.L.C. from Merck, Pfizer, and Gilead-United Medical. A.L.N., M.B., S.K.B., K.M.S., A.F.T., R.J.L., and N.A.K. are employees of Merck Research Laboratories and may own stock and/or stock options in the company.
Published ahead of print on 15 March 2010.